A Systematic Review of Human Bat Rabies Virus Variant Cases: Evaluating Unprotected Physical Contact with Claws and Teeth in Support of Accurate Risk Assessments

<div><p>In the United States and Canada, the most recent documented cases of rabies have been attributed to bat rabies viruses (RABV). We undertook this systematic review in an effort to summarize and enhance understanding of the risk of infection for individuals who have been potentially exposed to a suspect or confirmed rabid bat. United States rabies surveillance summaries documented a total of 41 human bat-rabies virus variant verified non-transplant cases between 1990 and 2015. All cases were fatal. Seven (17.1%) of 41 cases reported a bite from a bat. Ten (24.3%) cases had unprotected physical contact (UPC); these included seven cases that had a bat land or crawl on them (contact with claws) and one case that touched a bat’s teeth. Seven (17.1%) cases had probable UPC. Insectivorous bat teeth are extremely sharp and highly efficient for predation upon arthropod prey. Bats also have sharp claws on the end of their thumbs and feet. One of the most common bat RABV variants has an ability to replicate in non-neural cells. Questioning individuals about unprotected contact with bat teeth and claws (including a bat landing or crawling on a person) may help identify additional exposures.</p></div

Evolutionary lability of viral substitution rates in the rabies virus phylogeny.

<p>(A) Bayesian phylogenetic tree of bat rabies viruses with viral lineage names and climatic regions denoted in black (TE: temperate; ST: subtropical; TR: tropical). Host-associated lineages are condensed to triangles connecting the most recent common ancestor to the sampled branches. Lineages are colored along a blue (slowest) to red (fastest) continuum according to evolutionary rate in CP₃ using estimates from the Independent Lineage Models (ILMs). Bayesian posterior support values (>0.70) are given above branches to the lineage level only. All colored lineages received Bayesian posterior support values of ≥0.91. (B) Frequency histogram of expected values of Blomberg's <i>K</i> from 5000 random assignments of substitution rates estimated from the ILM to lineages. Dashed lines indicate 95% bounds of the null distribution and diamonds denote the median values of <i>K</i> for the randomized rate model, RRM (gray), the ILMs (blue), and the HPM (red).</p

Predictors of viral evolutionary rate from the Bayesian hierarchical phylogenetic model.

<p>(A) Effect sizes (<i>β</i>) on a log scale for each predictor were conditioned on the inclusion of that term in the model (i.e., <i>β</i> | <i>δ</i> = 1). Climatic region, coloniality, seasonal inactivity and long distance migration were categorical variables. Horizontal lines are the 95% highest posterior density intervals on conditional effect sizes and squares (median effect sizes) are proportional to effect sizes. (B) Violin plot showing the effect of climatic region on viral evolutionary rate. White points, black boxes and whiskers indicate the median, inter-quartile range and the total range of values for that group, respectively. The gray shading shows the probability density of evolutionary rate at different values.</p

Confirmed Cases of Non-Transplant Human Rabies attributed to a Bat RABV, United States, 1990 to 2015).

<p>Confirmed Cases of Non-Transplant Human Rabies attributed to a Bat RABV, United States, 1990 to 2015).</p

Heterogeneity in evolutionary rates of host-associated bat rabies viruses.

<p>Median substitutions per site per year in the 3^rd codon position of the nucleoprotein gene for estimates generated by the HPM (filled circles) and ILMs (open circles). Colors and dashed gray lines distinguish bat genera as indicated below the x-axis. Credible intervals denote the 95% highest posterior density interval on evolutionary rate.</p

Selected characteristics related to non-transplant cases of bat RABV reported in humans in the United States, 1990–2015.

<p>Selected characteristics related to non-transplant cases of bat RABV reported in humans in the United States, 1990–2015.</p

Flow Diagram for Systematic Review of Human Rabies Bat Rabies Virus Variant Cases*.

<p><i>Adapted from</i>: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). <i>P</i>referred <i>R</i>eporting <i>I</i>ems for <i>S</i>ystematic Reviews and <i>M</i>eta-<i>A</i>nalyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:<a href="http://dx.doi.org/10.1371/journal.pmed1000097" target="_blank">10.1371/journal.pmed1000097</a><b>For more information, visit</b><a href="http://www.prisma-statement.org" target="_blank">www.prisma-statement.org</a>.</p

Comparison of Biotinylated Monoclonal and Polyclonal Antibodies in an Evaluation of a Direct Rapid Immunohistochemical Test for the Routine Diagnosis of Rabies in Southern Africa

<div><p>The major etiological agent of rabies, rabies virus (RABV), accounts for tens of thousands of human deaths per annum. The majority of these deaths are associated with rabies cycles in dogs in resource-limited countries of Africa and Asia. Although routine rabies diagnosis plays an integral role in disease surveillance and management, the application of the currently recommended direct fluorescent antibody (DFA) test in countries on the African and Asian continents remains quite limited. A novel diagnostic assay, the direct rapid immunohistochemical test (dRIT), has been reported to have a diagnostic sensitivity and specificity equal to that of the DFA test while offering advantages in cost, time and interpretation. Prior studies used the dRIT utilized monoclonal antibody (MAb) cocktails. The objective of this study was to test the hypothesis that a biotinylated polyclonal antibody (PAb) preparation, applied in the dRIT protocol, would yield equal or improved results compared to the use of dRIT with MAbs. We also wanted to compare the PAb dRIT with the DFA test, utilizing the same PAb preparation with a fluorescent label. The PAb dRIT had a diagnostic sensitivity and specificity of 100%, which was shown to be marginally higher than the diagnostic efficacy observed for the PAb DFA test. The classical dRIT, relying on two-biotinylated MAbs, was applied to the same panel of samples and a reduced diagnostic sensitivity (83.50% and 90.78% respectively) was observed. Antigenic typing of the false negative samples indicated all of these to be mongoose RABV variants. Our results provided evidence that a dRIT with alternative antibody preparations, conjugated to a biotin moiety, has a diagnostic efficacy equal to that of a DFA relying on the same antibody and that the antibody preparation should be optimized for virus variants specific to the geographical area of focus.</p></div

Ngorongoro_Base_Case

Model code for Ngorongoro in base case

Phylogenetic representation of the genetic relationship between the rabies virus-positive sample (711/12) and representative canine and mongoose rabies virus variants circulating in southern Africa.

<p>Phylogenetic representation of the genetic relationship between the rabies virus-positive sample (711/12) and representative canine and mongoose rabies virus variants circulating in southern Africa.</p